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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a GLP reproductive and developmental toxicity screening study (similarly to OECD Guideline 421) in rats with read-across substance coriander oil, NOAEL for maternal toxicity and developmental toxicity = 500 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
28 June to 05 August 1988
Justification for type of information:
See read-across justification in section 13
Reason / purpose:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Clinical observations that occurred at dosage-dependent incidences and were considered to be effects of the test substance included excess salivation (250, 500 and 1000 mg/kg bw/day dosage groups), urine-stained abdominal fur, ataxia, and decreased motor activity (1000 mg/kg bw/day dosage group). Excess salivation occurred for the low and middle dosage group rats during the premating and gestation periods. High dosage group rats had excess salivation occur during the premating, gestation and lactation periods, as well as additional clinical observations occur during the premating and gestation periods. The number of rats with excess salivation was significantly increased (P≤0.05 to P≤0.01) in the middle and high dosage groups, as compared with the control group number. At 1000 mg/kg bw/day dosage group, the number of rats that also had urine stained abdominal fur, in addition to excess salivation, was significantly increased (P≤0.01), in comparison with the control group number during the premating period.
All other clinical observations were considered unrelated to the test substance. Red vaginal exudate, noted for one high dosage group rat on day 0 of gestation, was considered to be the result of trauma incurred during mating. A mass in the left inguinal area, that was probably a galactocele, was evident for one middle dosage group rat from day 0 of gestation through necropsy on day 4 post-parturition. Limited areas of alopecia occurred at biologically comparable incidences in the rats (one rat in each of the low, middle and high dosage groups).
Mortality:
no mortality observed
Description (incidence):
No deaths occurred during the conduct of this study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Premating:
Administration of the 1000 mg/kg bw/day dosage of test substance to the rats inhibited body weight gain prior to cohabitation. Significant (P≤0.01) weight loss occurred for the 1000 mg/kg bw/day dosage group after the first dosage was given. Between days 1 and 2 of study, rats in the control, low, middle and high dosage groups had average body weight changes of +2.8, +3.8, +2.7 and -6.0++ g, respectively. In these same respective groups, average body weight gains between days 1 and 7 of study were +17.2, +18.7, +19 .1 and +13 .1 g. Body weights on day 7 of study averaged 246.8, 247.1, 246.0 and 244.4 g in the four respective groups.

Gestation
Although the effect was not clearly dosage-dependent, possibly reflecting differences in litter sizes, biologically remarkable increases in average body weight gains occurred for pregnant rats in each group given test substance, as compared with the control group value. These increases in average maternal body weight gains were statistically significant (P≤0 .05) for the low and high dosage group rats between days 6 and 14 of gestation and resulted in significantly (P≤0.05 to P≤0.01) increased average maternal body weights on days 14 and 16 of gestation.
In the control, low, middle and high dosage groups, respectively, maternal body weights averaged 251.5, 255.3, 252.4 and 259.5 g on day 0 of gestation, 326.7, 347.3**, 339.6 and 351.3** g on day 14 of gestation, and 347.8, 364.8*, 353.7 and 368.4* g on day 16 of gestation. On day 21 of gestation, maternal body weights averaged 419.1, 450.8, 434.6 and 442.8 g in these same respective groups. Between days 6 and 14 of gestation, maternal body changes averaged +44.3, +55.0*, +47.3 and +53.1* g in the control, low, middle and high dosage groups, respectively. Maternal body weight changes between days 0 and 21 of gestation averaged +167.9, +195.6, +182.1 and +183.3 g in these same respective groups.

Lactation
At the beginning of the lactation period, each group given test substance weighed more than the control group. During the four-day post-parturition period, the effect of the test substance that caused weight gain and increased feed consumption during gestation decreased in severity, although it remained present. Maternal body weights averaged 305.2, 328.2, 330.6 and 333.1 g, in the four respective groups on day 1 of lactation, and 310.5, 332.0, 326 .9 and 326.3 g on day 4 of lactation. Between days 1 and 4 post-parturition, dams in the control, low, middle and high dosage groups, respectively, gained +5.3, +3.8, -3.7 and -4.6 g.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Premating:
Feed consumption values were unaffected by administration of test substance to the rats during the premating period. The differences that occurred were neither biologically important nor statistically significant among the four groups (P>0.05). In the four respective groups, feed consumption averaged 16.1, 16.5, 15.6 and 15.6 g/day. Feed consumption relative to body weight values averaged 67.4, 69.1, 66.0 and 65.6 g/kg/day for the rats in these same respective dosage groups.

Gestation:
Feed consumption values (g/day and g/kg/day) were significantly (P≤0.05 to P≤0.01) increased for the pregnant rats in each group given the test substance, as compared with the control group values. These increases in feed consumption during gestation were the possible cause of the increased weight gain during gestation that occurred for the rats given the test substance, as compared with the control group rats. It is noteworthy that not only were absolute feed consumption values (g/day) increased, but that the feed consumption relative to body weight values (g/kg/day) were also increased, indicating that the rats consumed even more feed than was necessary to maintain their body weights.
In the control, low, middle and high dosage groups, respectively, dams consumed 20.5, 23.1**, 22.6* and 23 .5** g/day between days 0 and 20 of gestation. In these same respective groups, feed consumption relative to weight values averaged 65.5, 70.7*, 70.6* and 71.4** g/kg/day between days 0 and 20 of gestation.

Lactation:
Feed consumption was increased for the middle and high dosage groups during the four-day lactation period, as compared with the control group values. Between days 1 and 4 post-parturition, absolute maternal feed consumption averaged 25.0, 25.0, 29.3 and 27.8 g/day in the four dosage groups, respectively. Maternal feed consumption relative to body weight values averaged 81.6, 75.3, 88.5 and 84.2 g/kg/day during the four-day post-parturition period for these same respective groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
Dosages of test substance as high as 1000 mg/kg bw/day did not adversely affect the reproductive performance of the female rats. In the 0(vehicle), 250, 500 and 1000 mg/kg bw/day dosage groups, respectively, 10, 8, 9 and 10 rats mated and were pregnant. These incidences of mating and pregnancy are within the range observed historically.
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Administration of the 1000 mg/kg bw/day dosage of test substance to the dams increased in utero and postnatal deaths of the offspring, as compared with the control group values.
All pregnant dams delivered one or more live pups. Implantation averages were similar for all groups (there were averages of 16.9, 17.0, 16.3 and 16.4 implantations per pregnant dam in the control, low, middle and high dosage groups, respectively). Delivered live litter sizes averaged 15.3, 16.0, 15.0 and 12.8 pups in the four respective groups, indicating that in utero deaths (resorptions) were increased for the high dosage group.
Pup mortality was significantly (P≤0.01) increased for litters of dams given the 1000 mg/kg bw/day dosage of test substance, as compared with the control group value. One dam had each of its five live born pups die before weighing on day 1 of lactation (the dam had a total of 16 implantation sites in utero). In the control, low, middle and high dosage groups, respectively, 97.4, 98.4, 97.8 and 87.5%** of the liveborn pups survived four days. By day 4 post-parturition, there were averages of 14.9, 15.8, 14.7 and 11 .2 surviving pups per litter. The increased incidences of clinical observations for the high dosage group pups were related to morbidity.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Dosages of test substance as high as 1000 mg/kg bw/day did not adversely affect pup body weights.
Sexual maturation:
no effects observed
Description (incidence and severity):
Dosages of test substance as high as 1000 mg/kg bw/day did not adversely affect the durations of gestation and pup sex ratios.
Other effects:
no effects observed
Description (incidence and severity):
No anatomical malformations or variations were revealed by external examination or necropsy of the pups in this study.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no

None

Conclusions:
Under the test conditions, the NOAEL for maternal toxicity was 500 mg/kg bw/day based on altered body weight and food consumption at 1000 mg/kg bw/day. Increases in bodyweight and food consumption, not considered to represent a relevant adverse toxicological effect of the treatment, were observed at 250 mg/kg bw/day. The NOEL for developmental toxicity was 500 mg/kg bw/day based on the smaller live litter sizes (in utero deaths) at 1000 mg/kg bw/day.
Executive summary:

In a Reproduction / Developmental Toxicity Screening Test conducted similarly to OECD Guideline 421 and in compliance with GLP, test substance was administered to groups of Crl: CD® (SD) BR rats (10 females/dose) at 0, 250, 500 and 1000 mg/kg bw/day by oral (gavage) for seven days prior to and then through cohabitation (maximum of seven days), gestation, delivery and a four-day lactation/post-parturition period. Clinical signs, body weight change, food consumption were monitored during the study. All animals were subjected to a gross necropsy examination. All litters were examined for number, viability, body weight, sex ratio and external morphology of the pups. Delivered pups were additionally examined for viability, clinical observations and body weight during a four-day post-parturition period.

No female rats died during the conduct of this study. All treated group rats showed excessive salivation; this observation was statistically significant at 500 and 1000 mg/kg bw/day when compared with the control group. At 1000 mg/kg bw/day, urine-stained abdominal fur occurred during the premating period, and one or two rats in this dosage group had ataxia and/or decreased motor activity occur infrequently during the premating and/or gestation periods. No other clinical or necropsy observations for the rats in this study were considered effects of the test substance.

 

Biologically remarkable decreases in body weight gain and food consumption occurred at 1000 mg/kg bw/day during the premating period, with significant weight loss evident for this group after the first dosage was given. During gestation, biologically remarkable increases in weight gain and food consumption occurred in all treated groups when compared with the control group. Statistically significant increases in body weight gain at 250 and 1000 mg/kg bw/day, and statistically significant increases in absolute (g/day) and relative (g/kg/day) food consumption in all treated groups when compared with the control group. These effects remained present but decreased in severity during the lactation period.

 

No adverse effect on the reproductive performance was observed at up to 1000 mg/kg bw/day. There were no dosage-dependent or statistically significant differences in duration of cohabitation, pregnancy incidences or implantation averages among the four groups. All pregnant dams delivered one or more live pups. At 1000 mg/kg bw/day, in utero deaths, evident as a biologically remarkable decrease in delivered live litter size, and a statistically significant increase in pup mortality, with associated observations of pup morbidity were observed.

 

At 1000 mg/kg bw/day, no adverse effect on the duration of gestation, pup sex ratios, pup body weights or the gross morphology of the pups were observed.

 

Under the test conditions, the NOAEL for maternal toxicity was 500 mg/kg bw/day based on altered body weight and food consumption at 1000 mg/kg bw/day. Increases in bodyweight and food consumption, not considered to represent a relevant adverse toxicological effect of the treatment, were observed at 250 mg/kg bw/day. The NOEL for developmental toxicity was 500 mg/kg bw/day based on the smaller live litter sizes (in utero deaths) at 1000 mg/kg bw/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a Reproduction / Developmental Toxicity Screening Test conducted similarly to OECD Guideline 421 and in compliance with GLP, test substance was administered to groups of Crl: CD® (SD) BR rats (10 females/dose) at 0, 250, 500 and 1000 mg/kg bw/day by oral (gavage) for seven days prior to and then through cohabitation (maximum of seven days), gestation, delivery and a four-day lactation/post-parturition period. Clinical signs, body weight change, food consumption were monitored during the study. All animals were subjected to a gross necropsy examination. All litters were examined for number, viability, body weight, sex ratio and external morphology of the pups. Delivered pups were additionally examined for viability, clinical observations and body weight during a four-day post-parturition period.

No female rats died during the conduct of this study. All treated group rats showed excessive salivation; this observation was statistically significant at 500 and 1000 mg/kg bw/day when compared with the control group. At 1000 mg/kg bw/day, urine-stained abdominal fur occurred during the premating period, and one or two rats in this dosage group had ataxia and/or decreased motor activity occur infrequently during the premating and/or gestation periods. No other clinical or necropsy observations for the rats in this study were considered effects of the test substance.

 

Biologically remarkable decreases in body weight gain and food consumption occurred at 1000 mg/kg bw/day during the premating period, with significant weight loss evident for this group after the firstdosage was given. During gestation, biologically remarkable increases in weight gain and food consumption occurred in all treated groups when compared with the control group. Statistically significant increases in body weight gain at 250 and 1000 mg/kg bw/day, and statistically significant increases inabsolute (g/day) and relative (g/kg/day) food consumption in all treated groups when compared with the control group. These effects remained present but decreased in severity during the lactation period.

 

No adverse effect on the reproductive performance was observed at up to 1000 mg/kg bw/day. There were no dosage-dependent or statistically significant differences in duration of cohabitation, pregnancyincidences or implantation averages among the four groups. All pregnant dams delivered one or more live pups. At 1000 mg/kg bw/day, in utero deaths, evident as a biologically remarkable decrease in delivered live litter size, and a statistically significant increase in pup mortality, with associated observations of pup morbidity were observed.

 

At 1000 mg/kg bw/day, no adverse effect on the duration of gestation, pup sex ratios, pup body weights or the gross morphology of the pups were observed.

 

Under the test conditions, the NOAEL for maternal toxicity was 500 mg/kg bw/day based on altered body weight and food consumption at 1000 mg/kg bw/day. Increases in bodyweight and food consumption, not considered to represent a relevant adverse toxicological effect of the treatment, were observed at 250 mg/kg bw/day. The NOEL for developmental toxicity was 500 mg/kg bw/day based on the smaller live litter sizes (in utero deaths) at 1000 mg/kg bw/day.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

In a Reproduction / Developmental Toxicity Screening Test conducted similarly to OECD Guideline 421, no adverse effect on the reproductive performance was observed at up to 1000 mg/kg bw/day in females. However, maternal toxicity was observed at 1000 mg/kg bw/day (ataxia and/or decreased motor activity in pre-mating and gestation periods, significant decreases in bodyweight gain and food consumtpion with significant weight loss during the pre-mating period) associated with a decrease in live litter size at this dose level. As no adverse effects on reproductive performance and the development of pups were observed up to evident maternal toxicity, the registered substance does not need to be classified for reproductive and developmental toxicity according to the Regulation (EC) No. 1272/2008.